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Discussion and analysis of the major trials in invasive aspergillosis. David W. Denning Director, National Aspergillosis Centre University Hospital of South Manchester [Wythenshawe Hospital] The University of Manchester Myconostica Ltd. Disclosures. Invasive aspergillosis.

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discussion and analysis of the major trials in invasive aspergillosis

Discussion and analysis of the major trials in invasive aspergillosis

David W. Denning

Director, National Aspergillosis Centre

University Hospital of South Manchester [Wythenshawe Hospital]

The University of Manchester

Myconostica Ltd

slide3

Invasive aspergillosis

IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327

slide4

Why most and not all?

Invasive aspergillosis

IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327

slide5

Arguments for not using voriconazole

  • Amphotericin B is a broader spectrum agent
frequency of mucormycosis in leukaemia
Frequency of mucormycosis in leukaemia

391 pts with leukaemia (225 with AML) and a filamentous fungal infection

80% neutropenia for >14 days, and 71% neutropenic at time of diagnosis

85% pulmonary infection

Antemortem diagnosis in 79%

Aspergillus 296 (76%)

Mucorales 45 (11.5%)

Fusarium 6

Other 4

Unidentified in 40

Overall mortality in 3 months 74%, 51% attributable

Pagano et al, Hemtaologia 2001;86:862

slide7

Intrinsic and acquired resistance among the Aspergilli

Amphotericin B resistance

A. flavus

A. terreus

A. nidulans

Azole resistance

A. fumigatus

A. niger

antifungal susceptibility of aspergillus nidulans
Antifungal susceptibility of Aspergillus nidulans

MIC90 ranges (μg/mL)

Amphotericin B 4 1–8 (52.3% ≥4)

micafungin 0.062 0.062- 0.125

itraconazole 2 0.25–4

voriconazole 2 0.062–2

posaconazole 1 0.25–1

Peláez et al, ECCMID 2009; P1297

slide9

Caspofungin

Voriconazole

Posaconazole

% frequency

75 5 5 2 1101 1

Filamentous fungi and antifungal drug activity

Highly active

Scedosporium apiospermum

Very active

Scedosporium prolificans

Paeciilomyces varioti

Paeciilomyces lilanicus

Active

A. fumigatus

Fusarium spp

A. terreus

A. nidulans

A. flavus

Mucorales

Inactive

A. niger

Amphotericin B

slide10

Arguments for not using voriconazole

  • Amphotericin B is a broader spectrum agent – No
  • AmBisome is equivalent to voriconazole in IA
randomised study of invasive aspergillosis with voriconazole versus amphotericin b

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13%

21%

Randomised study of invasive aspergillosis with voriconazole versus amphotericin B

391 pts received either

1) Voriconazole 4 mg/d BID (after loading) for 12wks (or OLAT)

or 2) AmB 1.0 mg/kg/d for 12wks (or OLAT)

mITT analysis

Success (%) Severe AEs (%) Renal tox (%) Died (all) (%)

Vori 53 13 1 29

AmB 32 24 10 42

Herbrecht, Denning et al, NEJM 2002;347:408

survival after primary rx with amphotericin b or voriconazole

100

80

60

Survival (percent)

40

Voriconazole

Amphotericin B

20

0

0

2

4

6

8

10

12

Weeks

Number of patients at risk

144 131 125 117 111 107 102 Voriconazole

133 117 99 87 84 80 77 Amphotericin B

Overall logrank test p=0.015

Survival after primary Rx with Amphotericin B or Voriconazole

Herbrecht, Denning et al, NEJM 2002;347:408

impact of second line treatment after voriconazole versus amphotericin b

Impact of second line treatment after voriconazole versus amphotericin B

Success (CR+PR)/Total (%) VoriconazoleAmpho B

Initial randomised Rx only 51/99 (51) 1/26 (4)

Patients who switched Rx 25/52 (48) 41/107 (38)

Lipid Ampho B 5/14 (36) 14/47 (38)

Itraconazole 11/17 (65) 18/38 (50)

Combination 0/1 0/9

Reason for switch

Intolerance 8/16 (50) 27/72 (38)

Insufficient clinical response 5/19 (26) 4/21 (19)

Chronic suppression 11/14 (79) 6/10 (60)

Overall success 76/144 (53) 42/133 (32)

Patterson et al, Clin Infect Dis 2005;41:1448

randomised study of invasive aspergillosis with amphocil versus amphotericin b

Randomised study of invasive aspergillosis with Amphocil versus amphotericin B

174 pts received either

1) Amphocil 6 mg/d for >2wks after symptoms gone

or 2) AmB 1.0 – 1.5 mg/kg/d >2wks after symptoms gone

70/174 (40%) in high risk (HSCT, liver Tx, AIDS, brain)

ITT analysis

Success (%) Tox (%) Renal tox (%) Died (due to IA)(%)

Amphocil 13 83 23 59 (22)

AmB 15 83 41 67 (20)

Bowden et al Clin Infect Dis 2002;35:359

slide15

Response rates to 2 Ambisome doses in invasive aspergillosis in neutropenia

100

90

80

70

Response

Rate %

60

Clinical

Radiological

50

Radiological

Clinical

40

30

20

10

0

1mg/kg

4mg/kg

Ellis et al, Clin Infect Dis 1998;27:1046

slide16

High-dose liposomal amphotericin B

Maximally tolerated dose study, 7.5 - 15mg/kg daily

44 patients, 21 proven / probable mould infection

MTD >15mg/kg

Responses in MITT, >7d Rx

7.5 10 12.5 15 mg/kg All (%)

Response rates (CR/PR) 5/7 3/7 4/5 4/12 16/29 (55)

Failure 2/7 1/7 1/5 5/12 13/29 (45)

Walsh et al, AAC 2001;45:3487

randomised study of invasive aspergillosis with 2 doses of ambisome

Randomised study of invasive aspergillosis with 2 doses of AmBisome

339 pts randomised to receive either

1) L-AmB 3 mg/d for 2+wks (169 randomised; 107 in MITT)

or 2) L-AmB 10 mg/d for 2+wks (162 randomised; 94 in MITT)

44/201 (22%) high risk (HSCT, AIDS)

MITT analysis

CR + PR Stop Rx Renal tox Died

L-AmB 3 50% 20% 14% 28%

L-AmB 10 46% 32% 31% 41%

Cornely et al, Clin Infect Dis 2007;44:1289

ambiload trial results

Survival

L-AmB 3 mg/kg

L-AmB 10 mg/kg

p = 0.089

Weeks

AmBiload trial results

Response

LAmB 3 mg/kg (n = 107)

LAmB 10 mg/kg (n = 94)

P = NS

50

Overall Response

40

30

50 %

46%

20

10

0

End of Treatment

Cornely et al, Clin Infect Dis 2007;44:1289

slide22

Arguments for not using voriconazole

  • Amphotericin B is a broader spectrum agent – No
  • AmBisome is equivalent to voriconazole in IA – No
  • Patient was on itraconazole prophylaxis
slide23

Arguments for not using voriconazole

  • Amphotericin B is a broader spectrum agent – No
  • AmBisome is equivalent to voriconazole in IA – No
  • Patient was on itraconazole prophylaxis
prophylactic itraconazole
Prophylactic Itraconazole

Glasmacher & Prentice J Antimicrob Chemother 2005; 56 (Suppl 1): i23.

increased amb mics after pre exposure of a fumigatus to itraconazole
Increased AmB MICs after pre-exposure of A. fumigatus to itraconazole

Kontoyiannis AAC 2000;44:2915

slide26

Arguments for not using voriconazole

  • Amphotericin B is a broader spectrum agent – No
  • AmBisome is equivalent to voriconazole in IA – No
  • Patient was on itraconazole prophylaxis – No
  • The patient has cerebral aspergillosis
slide27

Cerebral aspergillosis and voriconazole (n=81)

Schwartz et al, Blood 2005, Ruhnke personal comunication

slide28

Arguments for not using voriconazole

  • Amphotericin B is a broader spectrum agent – No
  • AmBisome is equivalent to voriconazole in IA – No
  • Patient was on itraconazole prophylaxis – No
  • The patient has cerebral aspergillosis – No (beware interactions)
  • The patient might have azole resistant Aspergillus
azole resistance in manchester in a fumigatus

11%

5%

17%

7%

5%

3%

0%

0%

5%

7%

0%

0%

Azole resistance in Manchester in A. fumigatus

Howard et al, Emerg Infect Dis 2009;15:1068

slide31

Posaconazole MIC (mg/L)

Voriconazole MIC (mg/L)

Itraconazole MIC (mg/L)

Manchester azole MIC distributions

modified EUCAST method - 0.5 x 105 not 1-2.5 x 105 cfu/mL

Howard unpublished

slide32

Arguments for not using voriconazole

  • Amphotericin B is a broader spectrum agent – No
  • AmBisome is equivalent to voriconazole in IA – No
  • Patient was on itraconazole prophylaxis – No
  • The patient has cerebral aspergillosis – No (beware interactions)
  • The patient might have azole resistant Aspergillus – maybe
  • Major drug interactions
cytochrome p450 interactions
Cytochrome P450 interactions

Dodds Ashley & Alexander. Drugs Today 2006;41:393.

slide34

Arguments for not using voriconazole

  • Amphotericin B is a broader spectrum agent – No
  • AmBisome is equivalent to voriconazole in IA – No
  • Patient was on itraconazole prophylaxis – No
  • The patient has cerebral aspergillosis – No (beware interactions)
  • The patient might have azole resistant Aspergillus – maybe
  • Major drug interactions – yes sometimes
  • Renal failure
slide35

Arguments for not using voriconazole

  • Amphotericin B is a broader spectrum agent – No
  • AmBisome is equivalent to voriconazole in IA – No
  • Patient was on itraconazole prophylaxis – No
  • The patient has cerebral aspergillosis – No (beware interactions)
  • The patient might have azole resistant Aspergillus – maybe
  • Major drug interactions – yes sometimes
  • Renal failure – only IV therapy needed for any duration
  • My patient is a young child and I am worried about blood levels
voriconazole levels in children
Voriconazole levels in children

Pasqualotto et al, Arch Dis Child 2008;93:578

slide37

Combination therapy – invasive aspergillosis

Retrospective

AmB failures

Most HSCT

30/47 proven IA

Multivariate analysis

P=0.008 for combination and survival

Marr et al, Clin Infect Dis 2004:39:797

slide38

Arguments for not using voriconazole

  • Amphotericin B is a broader spectrum agent – No
  • AmBisome is equivalent to voriconazole in IA – No
  • Patient was on itraconazole prophylaxis – No
  • The patient has cerebral aspergillosis – No (beware interactions)
  • The patient might have azole resistant Aspergillus – maybe
  • Major drug interactions – yes sometimes
  • Renal failure – only IV therapy needed for any duration
  • My patient is a young child and I am worried about blood levels – yes use 7mg/Kg BD (200mg BD orally) and consider combination therapy with an echinocandin and measure levels
slide39

Choice of antifungal for aspergillosis

  • Priority sequence
  • Voriconazole (unless drug interaction)
  • AmBisome 3mg/Kg (if not ‘nephro-critical’)
  • OR
  • caspofungin/micafungin (if not neutropenic)
  • 3. Posaconazole (oral only, if no drug interactions)
  • 4. Itraconazole
slide40

When not to use voriconazole as primary therapy?

  • Absolute contraindications
  • Drug interactions (ie rifampicin, carbamazepine, phenytoin etc)
  • Voriconazole used as prophylaxis (but not itraconazole or posaconazole)
  • Resistance to voriconazole (esp zygomycosis, A. lentulus or azole resistance)
  • Relative contraindications
  • Renal failure (IV only)
  • Young children (need higher dose ?+ other agent)
  • Severe hepatic dysfunction
  • Interacting drugs (ie sirolimus)
slide41

Aspects of good care - aspergillosis

  • Start treatment as fast as possible, with voriconazole, if no contra-indications
  • If sinus, centrally located pulmonary, endocarditis, brain abscess or osteomyelitis, plan on surgery
  • Resolve neutropenia, if present, but don’t over correct
rapid neutrophil recovery invasive aspergillosis
Rapid neutrophil recovery & invasive aspergillosis

Todeschini et al, Eur J Clin Invest 1999;29:453

slide43

Aspects of good care - aspergillosis

  • Start treatment as fast as possible, with voriconazole, if no contra-indications
  • If sinus, centrally located pulmonary, endocarditis, brain abscess or osteomyelitis, plan on surgery
  • Resolve neutropenia, if present, but don’t over correct
  • Reduce steroids and other immunosuppressants as much as possible
  • Check voriconazole levels
  • If culture positive, arrange species ID and MICs
  • Repeat CT scan (and GM) at ~2 weeks if rapidly progressive disease and at ~4 weeks of subacute disease
slide44

Invasive aspergillosis refractory to voriconazole

  • Check plasma voriconazole levels and MICs
  • If neutropenic
  • Amphotericin B/AmBisome or posaconazole preferred
  • If not neutropenic
  • Echinocandin or
  • Posaconazole or
  • AmBisome 3mg/Kg (3rd choice)

IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327